Heterocyclic nitrogen-containing compounds having a 3:4:5-trimethoxybenzoyl substituent



United States Patent HETERQQXQL1G NHROGEN-CQNTA NING COM- POUNDS HAVING A 3:4:5-TRIMETHOXYBEN- ZOY'L SUBSTITUEND David John Drain and; Haydn Windsor Richard Williams;

W lwyn. G rden Ci y, England, gn rs to T-. J- Smit i" & Nephew" Limited, Yorks ire, g a d, a B h mpa y No :Drawingi- Application October 2, 1956. Serial N 0.- 613,367

4'c1aim chm-294.3

I O-O O n -O CH;

OCH; C

wherein Ris-a hydrogen atom or an alkoxy or alkylenedioxy group, such as methoxyl or methylenedioxyl,

It will beseen that, these compounds are. heterocyclic nitrogen-containing compounds; having a 3:,415-trimethoxybenzoyl substituent and that they resemble Reserpine in their orientation,

According to the process, of the present invention, the compounds of general Formula I areprepared by condensing phenylglutari'c anhydri'de or a nuclear substituted phenylglutaric anhydride with isovanillylamine, reducing the resulting glutarimide to the corresponding piperidine compound, e. g. with lithiumaluminum hydride, and then acylating the hydroxyl group of the isovanillyl residue with ameact-ive derivative of'3 :4':5"-trimethoxybenzoic acid, such as the acid chloride.

I 2,819,273 Patented. Jan. 7., 1958 Thel i'eaction proceeds as follows:

H: G\ I r 0h 00 I t I +mNonQ-oom OH v 6 I11 k t I 0H: OCH:

(INCH:

+ 0100 OCHa OCHa OCH:

OCO- -OCH3 CH; CH!

The invention also includes the intermediates of the general Formula IH.

EXAMPLE Isov'anillin oxime gms.) was dissolved in methanol (450 ml.) and water (300 ml.) was added. Sodium amalgam (700 gms. 4%) was added insmall pieces with stirring over a period of an hour. During the addition of the amalgam, the pH of the reaction mixture was maintained slightly acid (5.5-6.5) by the addition of"50% acetic acid and the temperature was kept below 35 C. by external cooling.

When the reduction had been completed, the solution was decanted from the mercury, filtered and acidified to Congo Red with concentrated hydrochloric acid. The solution was evaporatedto dryness under reduced pressure'in a water bath-at C.- andthe residue was ex t-racted'with boiling methylated spirit-(250 mt); After removing the sodium chloride, the alcohol extract was bulk of the product crystallised or was deposited as a evaporated to a syrup under reduced pressure and the sticky syrup. It was recrystalhsed from ethylalcohol. residue was dissolved in boihng methylated Spll'll'. (200 The following are details of products so obtained.

Substltnent Crude, Recrystalllscd Analysis on the phenyl Yield ring Percent Appearance M. P., 0. Requlres Found 70.1 70.3 65 Colourless needles. 170 5.88 5.99

N.-. 4.3 4.4 4-0011; 56 Small colourless uee- 67.6 67.6

as 4.2 o--- 67.6 67.4 3-0011; 45 Colourless prisms.-. 165-167 H--- 5. 05 5.06

N... 3.9 as G--. 67.6 67.7 2-0011: a 128-129 6.95 5.60

O-.- 65.0 64.8 3:4 0H,--- 46 Golourless platelets..-- 135-136 5.16 6.27

1 This product crystalllses lrom ethyl acetate/petroleum ether as colourless platelets. M. P 104-105" 0.

ml.). The solution was filtered and allowed to stand at 0 C. for 24 hours.

Yield 32436 gms. (56-64%), M. Pt. 188-191" C. (including a second crop obtained by working up the mother liquors).

Recrystallisation from ethanol/ether gave colourless crystals M. Pt. 190-2 C.

C H O NCl requires C 50.6% H 6.4% Cl 18.7%. Found: C 50.9% H 6.2% Cl 19.1%.

(b) Isovanillylamine The hydrochloride was dissolved in water (5 volumes (d) Substituted phenyl piperidines (III) i 1 The following are details of the products so obtained.

Substltuent Crude, Recrystalllsed Analysts" 1 on the phenyl Yield i ring Percent Appearance M. P., 0. Requires Found (1.. 76.7 76.8 None 75 Colourless needles..-- 1475-1453..-. g.-- 40CH;.--...-- -----do 126'128'(re- 0-; 73.4 73.5 solidifies. H--- 7.70 r 8.1 139440). N 4.3 3.0 O-.- 73.4-- 73.1 3-OCH| Colourlessprlsms...-- 120-130 H-.. 7.70 7.42

N--- 4.3 4.3 C..- i 73.4 73.2 2-OCHI colourless crystals.-. 152-153 H-.. G-.- 70.3 70.2 3:4 CH,... 37 Golourlessneedles....- 130441 H--- 6.8 7.1 0 I N--- 4.1 3.8

and the theoretical quantity of 5 N sodium hydroxide solution was added with stirring. The product was filtered oil and dried in a vacuum desiccator over phosphorus pentoxide. 90-95%, M. Pt. 153158- C.

Purified by recrystallisation from ethanol and sublimation under reduced pressure. M. Pt. 156-160 C.

C8H1102N requires C 62.6% H 7.18%. Found C 62.9% H 7.29%.

(c) Substituted-phenyl glutarimides (II).

Isovanillylamine (0.03 mole) and the p-substitutedphenyl-glutaric anhydride (0.03 mole) were added to xylene (90 ml.) and the mixture .was refluxed under a water-separator for 24 hours. The hot xylene solution was decanted from tarry impurities and on cooling the 75 induced to crystallisc.

(e) 3:4:5-trimethoxybenzoylated products-(1) h The 1-(3-hydroxy-4-methoxybenzyl) piperidine was dis solved in dry pyridine (2 /2-3 vols.) and3z4z5-trirnethoxybenzoyl chloride (1.05 molar proportions) was a dded in small portions with agitation. The reaction migrture was allowed to stand at room temperature for 3 hours and was then poured into water (ca. 30 volumes); In some cases the precipitated product could be obtained crystalline by triturating with a little alcohol and a second crop could be'obtained by extracting the aqueous solution with ether, while in other cases it was necessary to take the whole of the product into other and wash out most of the pyridine with'watcr before the product could be The following are details of the products so obtained. wherein R represents a monovalent substituent selected Substituent Crude, Recrystallised Analysis on the phenyl Yield ring Percent Appearance M. P., 0. Requires Found None 78 Colourless crystals 94-95 C..- 70.9 70.9

from ethanol or ey- H 6. 76 6.78 clohexaue/ethyl-aee- N-.- 2. 85 2. 8 tate.

69.1 68.7 4-O0H= 76 Needles from ethanol.. 109.5-110 Z6 2.35

69:1 esls 30GH; 61 Colonrless plates lrom 115.5-116 6.76 6.7 ethanol. 2. 7 2. 6 69.1 69.2 2-0011. 61 do 118.5-119 e. 76 6.46

67.3 67.4 3:4 0111.... 54 Colourless crystals 99-100 6.21 6. 31

0 from methanol. 2. 6 2. 7

We claim: from the group consisting of hydrogen atoms, methoxy 1. The compounds of the general formula: groups and methylenedioxy groups.

3. The compounds of the general formula:

OCH:

OCH; o-oo- OGH: 30 l OCH: OCH: 00113 wherein R represents a monovalent substituent selected from the group consisting of hydrogen atoms, methoxy 35 4. The compounds of the general formula:

groups and methylenedioxy groups.

2. The compounds of the general formula:

No references cited. 

1. THE COMPOUNDS OF THE GENERAL FORMULA: 